科学研究

甘莱成立于2019年9月,专注于开发非酒精性脂肪肝炎(NASH)领域相关创新药,满足国内外患者需求。甘莱为歌礼制药有限公司(1672.HK)旗下全资子公司。


甘莱有三款分别针对脂肪酸合成酶(FASN)、甲状腺激素ß受体(THRß)及法尼醇X受体(FXR)的处于临床阶段的非酒精性脂肪性肝炎候选药物及三种固定剂量复方制剂。针对FXR靶点的新药同时被开发用于原发性胆汁性胆管炎的治疗。


ASC40:口服脂肪酸合成酶(FASN)抑制剂


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ASC40在NASH患者中治疗的疗效及安全性

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Rohit Loomba et al. 2020, Hepatology 72; 103.EASL 2020 Oral Presentation


• ASC40显著抑制肝内新生脂肪合成(DNL),通过12周治疗可使61%的患者肝内脂肪水平降低超过30% 

• ASC40降低肝内炎症反应程度,降低血清ALT水平 

• ASC40改善TIMP1、PIIINP等纤维化标志物水平,延缓肝脏纤维化进程


ASC41:肝脏靶向THR-β受体激动剂

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• ASC41为肝脏靶向前体药物在肝脏内经CYP3A4代谢为有效活性成分ASC41-A

• ASC41-A靶向肝内THR-β受体,低剂量暴露于其他表达THR的器官,如甲状腺、肌肉、大脑、脂肪 

• 相较于MGL-3196, ASC41对THR-β 受体结合亲和力以及处理能力更强(6倍/22倍)

• 2 种不同的NASH动物模型试验中,ASC41显示出与10倍剂量Resmetirom (MGL-3196)相同的NAS评分和肝纤维化改善


ASC41 I 期临床试验数据


• 研究对象为65位低密度脂蛋白胆固醇(LDL-C)大于110 mg/dL的具有非酒精性脂肪性肝病(NAFLD)特征的受试者 

• 在单剂量递增的研究中,随着给药剂量从1 mg到20 mg,ASC41的体内药物暴露量(药代动力学)呈线性关系,且在高达20 mg的剂量组中仍表现出良好的安全性和耐受性 

• 在多剂量递增的临床研究中,经过14天每日口服一次ASC41片剂治疗后,给药组受试者的低密度脂蛋白胆固醇(LDL-C)和甘油三酯(TG)指标相对安慰剂组表现出具有临床意义和统计学显著性的降低,如下图所示:


ASC41 1期临床试验.png


• 在14天治疗中,ASC41在所有剂量组中无3级或以上不良事件、严重不良事件或提前停药事件发生 

• 在14天每日口服一次ASC41片剂的研究中,随着给药剂量从1 mg到5 mg,ASC41片剂的体内药物暴露量(药代动力学)呈线性关系


ASC42:法尼醇X受体(FXR)激动剂

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• FXR受体分布于肝脏、胰腺以及肠道中 

• ASC42靶向结合FXR受体,刺激胰腺增加胰岛素分泌; 

• 提高脂肪细胞及骨骼肌细胞对胰岛素敏感性增加外周组织对葡萄糖摄取并增加能耗 

• 增加肠道组织对FGF15/19的表达 

• 降低肝内甘油三酯,脂肪酸以及胆固醇的合成,促进肝内脂肪分解及脂肪酸氧化








学术发表


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ASC41, a thyroid hormone receptor β agonist, showed little drug interaction, significant lipid reduction and comparable pharmacokinetic profiles among Chinese and US healthy subjects and patients with non-alcoholic fatty liver disease (NAFLD): results from two phase 1 studies

2023年美国肝病研究协会(AASLD)年会(The Liver Meeting® 2023)海报11/2023
Human Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ASC42, a Novel Farnesoid X Receptor AgonistDrugs in R&D论文11/2023
A Phase I, single-dose study to evaluate the safety, tolerability, and pharmacokinetics of ASC43F, a fixed-dose combination oral tablet of ASC41, a thyroid hormone receptor Beta agonist, and ASC42, a farnesoid X receptor agonist in healthy subjects2022年美国肝病研究协会(AASLD)年会(The Liver Meeting® 2021)海报11/2022
ASC43F Tablet as a One pill, Once a   day Fixed dose Combination of ASC41 a THR-β Agonist, and ASC42 a FXR Agonist,   Demonstrated Comparable Dissolution Profiles and in vivo Pharmacokinetics VS   Single ASC41 and ASC42 Tablets2021年美国肝病研究协会(AASLD)年会(The Liver Meeting® 2021)海报11/2021
ASC42, a Novel Non-steroidal FXR   Agonist, Demonstrates a Normal Cholesterol Profile and Lack of Pruritus at   Therapeutic Doses in a 14-day Phase I Randomized, Double-blind, Placebo   Controlled Study in Healthy Volunteers2021年美国肝病研究协会(AASLD)年会(The  Liver Meeting® 2021)海报11/2021
A Phase Ib Study to Evaluate the   Safety, Tolerability and Pharmacokinetics of ASC 41 a THR-β Agonist, for   28-days in Overweight and Obese Subjects with Elevated LDL-C, a Population   with Characteristic s Of NAFLD2021年美国肝病研究协会(AASLD)年会(The  Liver Meeting® 2021)海报11/2021

Significant lipid lowering by ASC41, an oral tablet, liver-targeted THRβ agonist, in a phase I randomized, double-blind, placebo controlled single- and multiple-ascending dose study

欧洲肝病学会(EASL)年会   (International Liver Congress™ 2021)海报04/2021

Significant Improvement of NAFLD Activity Scores and Liver Fibrosis by ASC42, a novel non-steroidal FXR agonist, in High Fat Diet Induced NASH mice

欧洲肝病学会(EASL)年会   (International Liver Congress™ 2021)海报04/2021

Significant Improvement of NAFLD Activity Scores and Liver Fibrosis by ASC41, a Selective THR-β Agonist, in High Fat Diet Induced NASH SD Rats

欧洲肝病学会(EASL)年会   (International Liver Congress™ 2021)海报04/2021

Novel, first-in-class, fatty acid synthase inhibitor, TVB-2640 versus placebo demonstrates clinically significant reduction in liver fat by MRI-PDFF in NASH

2020年美国肝病研究协会(AASLD)年会(The   Liver Meeting® 2020)口头报告11/2020

Novel, first-in-class, fatty acid synthase inhibitor, TVB-2640 versus placebo demonstrates clinically significant reduction in liver fat by MRI-PDFF in NASH

欧洲肝病学会(EASL)年会(International Liver Congress™ 2020)口头报告08/2020

The FASN inhibitor TVB-2640 is efficacious in a new 3D human liver microtissue model of NASH

欧洲肝病学会(EASL)年会(International Liver Congress™ 2020)海报08/2020
Fatty Acid Synthase Inhibitor TVB-2640 Reduces   Hepatic de Novo Lipogenesis in Males With Metabolic AbnormalitiesHepatology   2020论文07/2020
Progressive   Reductions in Hepatic DNL with Increasing Doses of TVB-2640, a First-in-Class   Pharmacologic Inhibitor of FASNKeystone Symposium on Organ Crosstalk in Obesity and NAFLD海报01/2018
Establishing the foundation for a novel, first-in-class, fatty acid synthase inhibitor, TVB-2640, for the treatment of NASH欧洲肝病学会(EASL)年会 (International Liver Congress™   2017)海报04/2017